Arthritis is a debilitating disease suffered by populations in America and worldwide. In this disease, inflammation goes through phases of progression and resolution. However, to date, drug development has focused on blocking the progressive pathways. The significance of immune suppressive pathways that might resolve arthritis by feedback inhibition remains largely unexplored. The long-term goal of this project is to explore the importance of feedback inhibition. Our laboratory has been investigating the impact of nitric oxide inhibitors on a chronic infectious disease leishmaniasis. We found that nitric oxide (NO) acts as a negative feedback inhibitor for production of type I cytokines in this system. This phenomenon has also been observed in many other disease models, where inflammation and tissue damage is exacerbated in knockout mice that lack the NO producing enzyme, inducible nitric oxide synthase (iNOS). On the other hand, recent developments in the field of the nuclear transcription factor peroxisome proliferator-activated receptor-gamma (PPAR-gamma) have also revealed that the prostenoids, 15-dsoxy- 12,14- PGJ2 (15-PGJ2), is a potent agonist of PPAR-gamma. Though like PGE2, this molecule is a product of cyciooxygenase-2 (COX-2), it acts as an endogenous suppressor of inflammation. Therefore, the immediate goal of this project is to study the role of the two feedback inhibitors, NO and 15-PGJ2, in mediating feedback inhibition in arthrogenesis. We hypothesis that there are certain time points in the process when production of these inhibitors is essential for keeping inflammation in check. Henceforth, it is possible that the reason why most of the commonly prescribed NSAIDs can only provide anti-nociceptive and anti-inflammatory relief might be because they abolish production of 15-PGJ2 by COX-2. The specific aims of this pilot study are (1) to characterize the kinetics of gene expression of iNOS and COX-2 and the I production of NO and 15-PGJ2 in arthrogeneis, and (2) to determine how inhibiting the production of NO or 15-PGJ2 at initiation of arthritis or after the disease is symptomatic would differentially affect disease outcome. The experiment will be performed using the murine collagen-induced arthritis model. If feedback mechanisms become a new focus then a groundbreaking paradigm shift would have been made for the development of treatment for arthritis and other inflammation-induced tissue damages.